Angiogenesis is the development of new blood capillaries and vessels. This process occurs normally in a number of biological situations, including fetal development, menstruation, ovulation, placental development and the development of collateral blood vessels in areas of disease or ischemia, nerve regeneration, bone growth, and wound healing. All these events, especially fetal development, require the very rapid growth of endothelial cells and their migration and differentiation into a complex network of vessels.
In addition to angiogenesis, which takes place in the healthy individual, angiogenic events are involved in a number of pathological processes, notably tumor growth and metastasis, and other conditions in which blood vessels proliferation, especially of the microvascular system, is increased, such as diabetic retinopathy, psoriasis and arthropathies. Inhibition of angiogenesis is useful in preventing or alleviating these pathological processes.
Because of the crucial role of angiogenesis in so many physiological and pathological processes, factors involved in the control of angiogenesis have been intensively investigated.
Vascular endothelial cell growth factor (VEGF), which is also termed VEGF-A or vascular permeability factor (VPF), has been reported as a pivotal regulator of both normal and abnormal angiogenesis (Ferrara and Davis-Smyth, 1997; Ferrara, 1999). In addition, truncated forms of VEGF-D and VEGF-C have been shown to stimulate angiogenesis through binding to VEGFR-2 (WO2012/088563).
The stimulation of angiogenesis has also been shown with agonistic substances of Bradykinin B1 and B2 receptors (WO 02/17958).
Bradykinin (BK) is a nonapeptide of sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg, generated as a result of the activity of kallikreins, a group of proteolytic enzymes present in most tissues and body fluids, on kininogens. BK and related kinins, like Lys-BK (kallidin) and Met-Lys-BK are able to activate the bradykinin B2 receptor. The removal of the C-terminal Arg residue in BK or in kallidin (Lys-BK) generates desArg9-BK and desArg9-Lys-BK. These peptides are also kinins and are specific ligands of the bradykinin B1 receptor. Once released, kinins produce many physiological responses, including pain and hyperalgesia by stimulating C- and A-fibers in the periphery. There is also considerable evidence that kinins contribute to the inflammatory response.
Bradykinin, and its physiologically important related peptides described above exhibit physiological actions which qualify them as mediators of inflammatory reactions, hypotensive states, pain, hyperalgesia, cardiovascular and/or cerebral circulatory diseases, tissue repair, stem cell differentiation, angiogenesis, lymphangiogenesis, immune system cells modulation, sepsis, wasting states, diabetes, neurogenesis, cardiac function and remodeling, kidney function, neurogenesis, and tumor development (Marceau F. and Regoli D., 2004).
Although treatments exist, there remain significant unmet needs for efficient and better therapies for activating or inhibiting angiogenesis and preventing and/or treating inflammatory diseases, pain, hyperalgesia, cardiovascular and/or cerebral ischemic diseases, notably in term of improved efficacy, and diminution of side effects.